This program is focused upon ocular surface immune-mediated diseases. We recently completed a masked trial of Cyclosporine eye drops for the treatment of keratoconjunctivitis sicca. We found elevated and comparable conjunctival inflammatory cell sub-populations and markers of immune activation (MHC Class II and adhesion molecules) in patients with both Sjogrens' Syndrome, a systemic autoimmune disease, aas well as, in the common form of dry eye. Our research has provided tangible evidence of an inflammatory basis for dry eye and confirms the rationale of anti-inflammatory therapy for its treatment, which represents a significant change in treatment strategy for this disease. We have also reported several of our findings on the immunopathogenesis of conjunctival manifestations of keratoconjunctivitis sicca. In addition, we have published a novel manifestation of Wegener's granulomatosis, tarsal-conjunctival disease which is characterized by signficant conjunctival cicatrization, scarring and increased risk of visual loss. We have also been investigating the treatment of the autoimmune exocrinopathy, Sjogren's Syndrome, which is associated with a particularly severe form of dry eye, in collaboration with the NIDCR, in 3 masked, placebo-controlled trials of DHEA, Thalidomide and Etanercept treatment. All 3 trials have been completed and the papers submitted for publication. In addition, we have also continued to work on validation of outcome measures for ocular surface disease and have published our findings which willfacilitate the use of ocular surface vital dye staining as an outcome measure for clinical trials. This work is ongoing. In addtion, we have also identified women with Premature Ovarian Failure as a new population of patients at risk for the development of ocular surface disease. Compared to age-matched women, significantly more patients with Premature Ovarian Failure use ocular lubricants and have objective signs and symptoms of dry eye. These patients scored significantly worse than controls on all 3 symptom questionnaires used and showed significantly more eye damage measured by ocular surface vital dye staining using validated grading schemes. These findings suggest that the dysregulation of hormones and immunologic dysfunction seen in Premature Ovarian Failure may play a role in the pathogenesis of ocular surface disease in these patients. This paper has been accepted for publication by Archives of Ophthalmology.